Microglial degeneration in the aging brain - bad news for neurons?

Abstract

We have long promulgated the idea that microglial cells serve an entirely beneficial role in the central nervous system (CNS), not only as immunological sentinels to fend off potentially dangerous infections, but also as constitutively neuroprotective glia that help sustain neuronal function in the normal and especially in the injured CNS when microglia become activated. In recent years, we have reported on the presence of degenerating microglial cells, which are prominent in the brains of aged humans and humans with neurodegenerative diseases, and this has led us to propose a hypothesis stating that loss of microglia and microglial neuroprotective functions could, at least in part, account for aging-related neurodegeneration. In the current review, we sum up the many aspects that characterize microglial activation and compare them to those that characterize microglial senescence and degeneration. We also consider the possible role of oxidative stress as a cause of microglial degeneration. We finish up by discussing the role microglial cells play in terms of amyloid clearance and degradation with the underlying idea that removal of amyloid constitutes a microglial neuroprotective function, which may become compromised during aging.

Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment

“…It has been suggested that age-related neurodegeneration might not only be due to a loss of neuroprotective properties, but also the actual loss of microglia [40]. A recent hypothesis put forth to explain the phenotypic changes in aging microglia suggest that microglial senescence is triggered by an intracellular oxidative stress response due to enhanced intracellular accumulation of iron [41]. Under this hypothesis, an oxidative stress response, often attributed to microglia based primarily upon in vitro studies, would lead to senescence rather than activation.…”

In VivoMRI Mapping of Brain Iron Deposition across the Adult Lifespan

“…With aging, iron dysregulation occurs (Daugherty et al, 2015), resulting in a chain of events that, although not fully elucidated, appear to be largely deleterious: for example, insidious damage to the blood-brain barrier (Farrall and Wardlaw, 2009) and excessive free radical generation inducing oxidative stress (Poon et al, 2004) are mechanisms thought to be associated with age-and disease-related iron accumulation. In addition, it is also thought that microglial activation stimulates iron uptake from damaged cells and downregulates export to exacerbate iron imbalance (Rathore et al, 2012), thus compromising microglial neuroprotection (Streit et al, 2008) and increasing neurotoxicity (Block et al, 2007).…”

Studying neurodegenerative diseases in culture models

“…For example, the role of prostaglandins and underlying cell signaling after activation of lipopolysaccharide led to novel insights. [62][63][64][65][66] Since AD and PD are age-related disorders and microglia may change their functional properties in the aging brain, 67 protocols are in demand for the isolation of microglia from adult rodents. A few protocols exist; however, presently, literature is scarce on this topic.…”